ABSTRACT AD SUPPLEMENT. A model of sleep deprived neuropathology to study resilience to Alzheimer's disease (PARENT R01 AG057381. Physical resilience is a predictor of healthy aging in mice) Resilience to Alzheimer's disease (AD) is a well-known clinical and pathological observation, but the mechanisms involved are not known. Adequate sleep is a potential factor in maintaining resilience to neurodegenerative conditions such as AD. Sleep deprivation is a major health concern in developed countries and is associated with increasing age. Sleep disturbances increase the risk of dementia and AD and there is growing evidence that poor sleep leads to acceleration in the pathogenesis and progression of neurodegenerative disorders. A logical question is whether the prevention of sleep deprivation-induced neuropathology and cognitive impairment will enhance resilience to AD. We have developed an aging mouse model of short-term sleep deprivation that results in neurodegenerative changes and cognitive impairment and is prevented by a mitochondrial specific peptide. Therefore, this ?youthful? background would be expected to be more resistant (resilient) to development of AD induced neuropathology and dementia. The hypothesis of this supplemental proposal is that prevention of sleep-deprived neuropathology will enhance resilience to the early development of Alzheimer's disease. The specific aim is to investigate neuropathology and cognitive impairment in aging, sleep-deprived mice challenged with AAV A?42/P301Ltau. Cohorts will be treated with the mitochondrial specific peptide SS31 before and during sleep deprivation. All mice will be examined for cognition, neuropathology and molecular pathology. Because SS31 prevents the neuropathology and cognitive impairment induced by sleep deprivation, it is expected that SS31 will be able to prevent the development of A?42/P301Ltau pathology.